The initiating event in many myocardial infarctions (heart attacks) is the formation of a blood clot (thrombus) formed primarily of fibrin and blood platelets in the coronary artery. Formation of a fibrin/platelet blood clot in the coronary or other artery has serious clinical consequences. If the clot is large and/or remains in position for an extended period of time, extensive damage in the infarct zone (i.e., the area of coagulation necrosis which results from an obstruction of blood circulation) may result. Accordingly, the current treatment for myocardial infarction involves rapidly dissolving the occluding thrombus by administering a thrombolytic agent (i.e., an agent that is capable of lysing the thrombus) and, thereby, restoring blood flow through the affected blood vessel. Due in part to the urgent need to restore blood flow in an occluded vessel, the principal focus for treating conditions that are mediated by thrombus formation has been the discovery of new and better thrombus-dissolving drugs, e.g., urokinase, streptokinase, and tissue-type plasminogen activator (t-PA). Significantly less effort has been directed to the discovery and/or development of drugs that prevent or inhibit thrombus formation in the first instance.
The formation of a thrombus involves the conversion of a soluble plasma protein (fibrinogen) into an insoluble protein (fibrin). The conversion of fibrinogen to fibrin is catalyzed by the enzyme thrombin, in accordance with a mechanism that is known in the art. Platelets adhere to fibrinogen via their .alpha..sub.IIb .beta..sub.3 integrin receptors and therefore contribute to thrombus which is initiated by the formation of cross-linked fibrin. Thus, in general, the strategies proposed for preventing fibrin/platelet clot formation have involved either the administration of a "maintenance" level of a thrombolytic agent (e.g., t-PA) to reduce the likelihood of reocclusion following treatment of acute infarction and/or the administration of anticoagulants (e.g., heparin glycosaminoglycan) to inhibit or prevent fibrin clot formation in parts of the circulatory system by increasing the rate of inactivation of thrombin by anti-thrombin III.
In view of the demonstrated utility of blood clot dissolving agents in treating conditions that are mediated by thrombus formation and in view of the many side effects of heparin glycosaminoglycan, a need still exists to develop new and useful agents that inhibit or prevent thrombus formation in the first instance. Preferably, such agents would selectively inhibit thrombus formation at its earliest stages, thereby requiring administration of relatively low doses of the agent and minimizing the likelihood of side reactions that may be associated with the administration of a high dosage of the therapeutic agent.